Showing papers in "Trends in Endocrinology and Metabolism in 1993"
TL;DR: A continually responsive HPA axis, even under conditions of chronic stress, appears to be important for survival and there is an overall metabolic cost to the animal of maintaining continued activity in the HPAaxis during chronic stress.
Abstract: The hypothalamic-pituitary-adrenal (HPA) axis exhibits a circadian rhythm, activation by stress, and inhibition by corticosteroids. Activity in the HPA axis is very sensitive to inhibition by corticosteroids when they are administered exogenously. When stress-induced corticosteroid secretion occurs, however, normal activity in the HPA is not inhibited and may even be augmented. Experiments in rats have shown that stress also induces facilitation of subsequent activity in the HPA axis that appears to balance the inhibitory effects of corticosterone and thus maintains responsiveness to new, acute stresses in chronically stressed rats. Stress-induced facilitation of HPA axis activity may be mediated by a parallel stress-induced (CRH-dependent) increase in the capacity of brain noradrenergic cell groups to respond to acute stress. A continually responsive HPA axis, even under conditions of chronic stress, appears to be important for survival. Stress-induced increases in glucocorticoid secretion to levels sufficient to occupy glucocorticoid receptors enable appropriate thermoregulatory and cardiovascular responses to acute stress. There is, however, an overall metabolic cost to the animal of maintaining continued activity in the HPA axis during chronic stress.
326 citations
TL;DR: Seven receptors with highly homologous structural features have been discovered that belong to a new family of seven membrane-spanning receptors within the G-protein-linked receptor superfamily, and many have the unique property to activate the G(S) and at least one other G protein.
Abstract: Seven receptors with highly homologous structural features have recently been discovered that belong to a new family of seven membrane-spanning receptors within the G-protein-linked receptor superfamily. These seven all bind small peptide ligands, and many have the unique property to activate the G(S) and at least one other G protein.
298 citations
TL;DR: Six distinct insulinlike growth factor-binding proteins (IGFBP-1 to IGFBP-6) of core molecular mass 20-30 II have been identified, of which one, IGF BP-3, carries most of the circulating IGF-I and IGF-II in ternary complexes that also contain an acid-labile glycoprotein subunit.
Abstract: Six distinct insulinlike growth factor-binding proteins (IGFBP-1 to IGFBP-6) of core molecular mass 20-30 II have been identified, of which one, IGFBP-3, carries most o f the circulating IGF-I and IGF-II in ternary complexes that also contain an acid-labile glycoprotein subunit. Although the role of circulating IGFBP-3 in IGF stabilization and transport is becoming increasingly well understood, the functions of the other IGFBPs in the circulation are less clear, and some redundancy of function is possible. IGFBP-l, which is metabolically regulated by insulin and carbohydrates, may act as a counterregulator in blood glucose regulation and could also be important in targeting IGF delivery from the circulation to the tissues, while recent studies of IGFBP-2 physiology suggest that this protein may function as an additional IGF carrier when IGFBP-3 levels are inadequate. Research into the roles of circulating IGFBP-4, -5, and -6 is, as yet, poorly developed and will depend on the ready availability of analytical methods for these proteins.
183 citations
TL;DR: A complex network of receptor interaction has been unraveled that promises a better understanding of thyroid and retinoid hormone regulation of fundamental biologic processes and diseases.
Abstract: Biologic responses to retinoids and thyroid hormones are mediated by their intracellular receptor proteins. Many exciting advances have been made recently in understanding the molecular mechanism by which these receptor proteins operate. In contrast to the steroid hormone receptors that function predominantly as homodimers, thyroid hormone receptors (TRs)and retinoic acid receptors (RARs) require interaction with the retinoid X receptors (RXRs) for efficient DNA binding and transactivation. In addition, RXRs, in the presence of their specific ligands such as 9-cis RA, can form homodimers that recognize a subset of retinoic acid responsive elements (RAREs). The retinoid responses mediated by RXR homodimers and RAR-RXR heterodimers can be restricted by the COUP-TF orphan receptors that bind strongly to certain RAREs as homodimers. Thus, a complex network of receptor interaction has been unraveled that promises a better understanding of thyroid and retinoid hormone regulation of fundamental biologic processes and diseases.
119 citations
TL;DR: In this review, an attempt is made to summarize the recent progress made in the continuing effort to understand the regulation of feeding behavior by neuropeptides, particularly those that stimulate feeding.
Abstract: Neuroendocrine control of feeding behavior is multifactorial, involving a variety of peripheral and central signals. Neuropeptides, catecholamines, and serotonin constitute the signals of the feeding circuitry acting primarily in the brain, especially at the hypothalamic level. In this review, an attempt is made to summarize the recent progress made in our continuing effort to understand the regulation of feeding behavior by neuropeptides, particularly those that stimulate feeding. A special emphasis has been placed on a neuropeptide of the pancreatic polypeptide family-neuropeptide Y (NPY).
104 citations
TL;DR: There is increasing evidence that intracellular sulfation and desulfation can play a role in regulating the availability of active steroid hormones near target sites.
Abstract: Formation of steroid sulfates is catalyzed by sulfotransferase enzymes that are widely distributed and frequently of high specificity. Steroid sulfates cannot be described as being active hormones, but some serve in tissue sites as precursors of active steroids formed by enzymic cleavage of the sulfate group by sulfatase enzymes. There is increasing evidence that intracellular sulfation and desulfation can play a role in regulating the availability of active steroid hormones near target sites. There are strong indications for this regulation in the uterine compartment, in the liver, and in mammary cancer cells.
104 citations
TL;DR: The discovery of their activation by physiologic concentrations of fatty acids raises the question of whether fatty acids are ligands of PPARs, which would imply that nutritional fatty acids can act like hormones.
Abstract: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily like the steroid, thyroid, or retinoid hormone receptors, which are ligand-activated transcription factors regulating gene expression. PPARs mediate the induction of the enzymes of the peroxisomal and microsomal fatty-acid oxidation pathways by hypolipidemic drugs such as clofibrate and are probably also involved in the gene expression of other lipid-metabolism-associated proteins that are controlled by fibrate hypolipidemic drugs. That PPARs play an important role in the regulation of lipid metabolism is reinforced by the discovery of their activation by physiologic concentrations of fatty acids. This observation raises the question of whether fatty acids are ligands of PPARs, which would imply that nutritional fatty acids can act like hormones.
92 citations
TL;DR: It now is apparent that a family of closely related genes encode for 3β- hydroxysteroid dehydrogenase (3βHSD), and studies on the regulation of these genes are in their infancy, but the regulation appears multifactorial.
Abstract: It now is apparent that a family of closely related genes encode for 3β- hydroxysteroid dehydrogenase (3βHSD). Studies on the regulation of these genes are in their infancy, but the regulation appears multifactorial. The various 3βHSD genes are expressed principally in a tissue-specific manner likely involving separate mechanisms of regulation. To date, two human 3βHSD genes and their products have been characterized; type I is expressed in placenta, sebaceous glands, and several other nonendocrine tissues, whereas the type II isoform is the principal 3βHSD of adrenal cortex and gonads.
85 citations
70 citations
TL;DR: Five key emerging physiologic roles of PTHrP appear to act in an autocrine or paracrine fashion in normal embryogenesis and neonatal development, cellular growth and differentiation, reproduction and lactation, epithelial calcium transport, and smooth muscle relaxation.
Abstract: Parathyroid hormone-related protein (PTHrP) is the factor responsible for the syndrome of humoral hypercalcemia of malignancy. PTHrP is produced by a multitude o f normal as well as malignant cells, and exerts both classic parathyroid hormone (PTH)-like and PTH-unlike effects. The molecular cloning of the PTHrP gene, and the subsequent recognition of its widespread expression in normal tissues under normal physiologic conditions, has prompted intense inquiry into its biologic function. PTHrP appears to act in an autocrine or paracrine fashion in (a) normal embryogenesis and neonatal development, (b) cellular growth and differentiation, (c) reproduction and lactation, (d) epithelial calcium transport, and (e) smooth muscle relaxation. These five key emerging physiologic roles of PTHrP are the focus of this review.
65 citations
TL;DR: Therapeutic studies with NZB/W mice, as well as anecdotal evidence from a small number of patients, have provided evidence that PRL suppressive therapy may be beneficial in selected cases of autoimmune disease.
Abstract: A number of reports have shown that PRL is an immune-stimulating hormone that is capable of stimulating organ-specific inflammatory disease in humans. More recently, hyperprolactinemia has been associated with the active phase of the immune-complex-mediated autoimmune disease, systemic lupus erythematosus. The theory that PRL contributes substantially to disease activity was upheld in the NZB/W mouse model of spontaneous, hormone-sensitive lupus. Implanted pituitary glands resulted in hyperprolactinemia, accelerated proteinuria, high levels of circulating IgG, and premature death. Therapeutic studies with NZB/W mice, as well as anecdotal evidence from a small number of patients, have provided evidence that PRL suppressive therapy may be beneficial in selected cases of autoimmune disease.
TL;DR: In this paper, the selective properties of both types of analogues stem from altered receptor binding, blood protein binding, and rate of catabolism, leading to the name "non-calcemic analogues."
Abstract: Many new analogues of the vitamin-D hormone, 1 α,25-dihydroxy-vitamin D 3 [1 α,25-(OH) 2 D 3 ; calcitriol], have emerged that can mimic its various actions in classic calcium transport systems and/or in the regulation of cell proliferation and cell differentiation. Though some of these analogues have accentuated activity in cell differentiation assays in vitro, they lack appreciable "calcemic" activity in vivo, leading to the name "noncalcemic analogues." Several of these analogues are promising candidates for use in treatment of psoriasis and in tumor suppression, one of them, calcipotriol, being already widely approved for the former indication. New generations of calcemic analogues with altered pharmacokinetics are appearing for use in secondary hyperparathyroidism and osteoporosis. We believe that the selective properties of both types of analogues stem from altered receptor binding, blood protein binding, and rate of catabolism.
TL;DR: The coordinate responses of these genes to trophic hormones are not readily explained by a unifying mechanism, and their hormone responsive expression probably involves multiple promoter elements.
Abstract: Corticosteroid biosynthesis requires the concerted action of a related group of cytochrome P450 steroid hydroxylases. The genes encoding these steroid hydroxylases exhibit two distinct levels of transcriptional regulation: selective expression in steroidogenic cells and induction in response to trophic hormones. With respect to cell-selective expression, recent studies have identified a nuclear receptor protein expressed only in steroidogenic cells that is postulated to regulate the expression of all cytochrome P450 steroid hydroxylases through common promoter elements. In contrast, the coordinate responses of these genes to trophic hormones are not readily explained by a unifying mechanism, and their hormone responsive expression probably involves multiple promoter elements.
TL;DR: The related ACTH and melanocyte-stimulating hormone (MSH) receptors control adrenal steroidogenesis and pigmentation in response to an overlapping set of peptides derived from the proopiomelanocortin molecule.
Abstract: The related ACTH and melanocyte-stimulating hormone (MSH) receptors control adrenal steroidogenesis and pigmentation in response to an overlapping set of peptides derived from the proopiomelanocortin (POMC) molecule. The recent cloning of these receptors has already opened up a new understanding of their role in normal and pathologic functioning of the adrenal cortex, and of the process of pigmentation. The murine MSH receptor maps to a genetic locus called extension, a locus known since early in this century to control the relative amounts of the two major types of melanins: eumelanin and phaeomelanin. The highly variable pigmentation phenotypes resulting from different extension locus alleles are caused by structural mutations in the MSH receptor that alter the degree of its signal-transducing capacity. A mutation in the ACTH receptor in a patient with ACTH resistance has also recently been reported. It is likely that the etiology of this rare disease includes mutations that affect the functioning of the ACTH receptor.
TL;DR: Treatment with preoperative alpha- and beta-adrenergic blockade followed by surgical excision of the pheochromocytoma are associated with very low morbidity and mortality.
Abstract: Pheochromocytoma is a tumor frequently sought and rarely found. It is associated with spectacular cardiovascular disturbances and, when correctly diagnosed and properly treated, it is curable; when undiagnosed or improperly treated, it can be fatal. Catecholamine-producing tumors that arise from chromaffin cells of the adrenal medulla and sympathetic ganglia are termed pheochromocytomas and paragangliomas, respectively. However, the term pheochromocytoma has become the generic name for all catecholamine-producing tumors. The biochemical diagnosis is straightforward. The localization of pheochromocytoma has been greatly facilitated by advances in computerized imaging and meta-iodobenzylguanidine scanning. Treatment with preoperative alpha- and beta-adrenergic blockade followed by surgical excision of the pheochromocytoma are associated with very low morbidity and mortality.
TL;DR: In this article, a review summarizes the clinical and experimental evidence supporting the causal role of five key genes in thyroid oncogenesis, namely, ras, gsp, ret, and trk, and the tumor-suppressor gene TP53.
Abstract: Tumors of the human thyroid follicular cell demonstrate multiple "routes" and multiple stages of development, offering an unparalleled opportunity for correlating clinicopathologic tumor behavior with the underlying molecular genetic abnormalities. This review summarizes the clinical and experimental evidence supporting the causal role of five key genes in thyroid oncogenesis, namely, the oncogenes ras, gsp, ret, and trk, and the tumor-suppressor gene TP53. The nature of the somatic mutations is described and the likely mechanisms discussed by which they perturb cellular growth signal transduction to produce particular pathologic phenotypes. A model of thyroid oncogenesis is presented that suggests that the pattern of tumor development is determined by the nature of the initiating oncogenic event.
TL;DR: Current knowledge of the effects of altered thyroid status on the GH-IGF-I axis is presented, concentrating on the changes seen in IGF-I gene expression and circulating levels of GH and IGFBPs.
Abstract: There is a complex relationship between thyroid hormones, GH, and the insulin-like growth factors (IGFs). Thyroid hormones act at many sites from the hypothalamic control of GH release to the tissue expression of IGF-I and its binding proteins (IGFBPs). In this review, we present current knowledge of the effects of altered thyroid status on the GH-IGF-I axis, concentrating on the changes seen in IGF-I gene expression and circulating levels of GH and IGFBPs.
TL;DR: The nuclear localization of most steroid hormone receptors reflects a dynamic process: the receptor constantly diffuses out of the nucleus and is reimported by an active mechanism.
Abstract: The nuclear localization of most steroid hormone receptors reflects a dynamic process: the receptor constantly diffuses out of the nucleus and is reimported by an active mechanism. The outward movement from the nucleus of the receptors and of other nuclear proteins is also mediated by the nuclear localization signals.
TL;DR: Amylin action is similar to that of calcitonin, but lower in potency, and lower circulating concentrations of amylin in type-1 diabetes may cause the bone loss associated with this condition.
Abstract: Amylin, a 37-amino-acid long single-chain polypeptide, is structurally homologous to calcitonin and calcitonin gene-related peptide (CGRP). The peptide is secreted from pancreatic β cells and is thought to have an anti-insulin action. Here, we review the recently described effects of amylin on calcium homeostasis and discuss its possible role in bone conservation. Amylin is a potent hypocalcemic and antiresorptive peptide. Studies using isolated osteoclasts have revealed that amylin inhibits cell motility (Q effect), without affecting cell spread area or elevating cytosolic [Ca 2+ ]. Thus, amylin action is similar to that of calcitonin, but lower in potency. Lower circulating concentrations of amylin in type-1 diabetes may cause the bone loss associated with this condition.
TL;DR: This review focuses on the role of the factors acting on the ICE and other enhancer control elements in the establishment of cell-type-specific and physiologically regulated transcription of the insulin gene.
Abstract: Selective transcription of the insulin gene in pancreatic β cells is regulated by its enhancer, located between nucleotides -340 to -91 relative to the transcription start site. The activity o f the enhancer is controlled by both positive- and negative-acting cellular factors. Cell-type-specific expression is mediated principally by a single cisacting enhancer element, termed the insulin control element (ICE), which is acted upon by both these cellular activities. This review focuses on the role of the factors acting on the ICE and other enhancer control elements in the establishment of cell-type-specific and physiologically regulated transcription of the insulin gene.
TL;DR: GH and IGF-I may be part of a neuroendocrine immune axis that stimulates cellular proliferation of primary lymphoid organs (bone marrow, thymus) as well as stimulates activation of peripheral lymphocytes and macrophages to enhance specific immune responses.
Abstract: Growth hormone (GH) and insulinlike growth factor I (IGF-I) may be part of a neuroendocrine immune axis that stimulates cellular proliferation of primary lymphoid organs (bone marrow, thymus) as well as stimulates activation of peripheral lymphocytes and macrophages to enhance specific immune responses. GH can also stimulate production of thymic hormones and cytokines, and in this way impact on immune function. It is not clear whether GH and IGF-I act independently or whether the action of GH is mediated by local production of IGF-I by lymphocytes. Both GH and IGF-I and their receptors are present in lymphocytes. Thus, cells of the immune system may be important targets of the GH-IGF-I axis.
TL;DR: The identification of activating mutations of Gsa in liver, heart, and gastrointestinal tract of patients with MAS suggests a broader spectrum of clinical disease than previously appreciated.
Abstract: McCune-Albright syndrome (MAS) is characterized by the clinical triad of polyostotic fibrous dysplasia, cafe-au-lait pigmented skin lesions, and multiple endocrinopathies. The molecular basis of MAS is a mutation in G(s)alpha that results in constitutive activation of adenylyl cyclase in affected tissues. This mutation occurs during early embryogenesis, and therefore patients with MAS are mosaic. The identification of activating mutations of Gsa in liver, heart, and gastrointestinal tract of patients with MAS suggests a broader spectrum of clinical disease than previously appreciated.
TL;DR: The T(3)-induced increase in Na,K-ATPase subunit mRNA expression has been shown to be mediated by both transcriptional and post-transcriptional mechanisms.
Abstract: Active Na,K transport across plasma membranes (mediated by Na,K-ATPase) is stimulated by triiodothyronine (T 3 ) in all mammalian tissues responsive to thyroid hormone, and this stimulation has been proposed to account for a substantial fraction of thyroid thermogenesis. The enhancement of Na,K-ATPase activity by T 3 results from increased biosynthesis of Na,K-ATPase subunits and is associated with increased abundance of their encoding mRNAs. In certain target tissues, T 3 preferentially augments the expression of the α2 isoform of the enzyme (characterized by its high sensitivity to inhibition by cardiac glycosides). The T 3 -induced increase in Na,K-ATPase subunit mRNA expression has been shown to be mediated by both transcriptional and post-transcriptional mechanisms.
TL;DR: Three recent articles reviewed here provide examples of different mutations in this homeobox gene encoding a transcriptional activation protein that is vital to the embryologic development, survival, and differentiated function of somatotropes, lactotrope, and thyrotropes.
Abstract: The story of Pit-1 and hypopituitarism in humans provides an excellent example of pleiotrophism or multiple phenotypic effects resulting from a single genetic alteration. It shows how defects in this single gene cause the absence o f several pituitary hormones. Three recent articles reviewed here provide examples of different mutations in this homeobox gene encoding a transcriptional activation protein that is vital to the embryologic development, survival, and differentiated function of somatotropes, lactotropes, and thyrotropes.
TL;DR: It was shown that LDL enhanced the uptake of T(4) by cultured fibroblasts in which the LDL receptors were expressed, and a number of possible physiologic consequences of thyroid hormonelipoprotein interactions have been put forward as topics for further investigation.
Abstract: A small but significant portion of the thyroid hormones that circulate in human plasma is associated with lipoproteins. Although the major lipoprotein carrier is HDL, the role of these interactions on T 4 entry into cells was tested first with LDL and human fibroblasts because of the well-characterized LDL receptors and the availability of cells with genetically absent receptors. It was shown that LDL enhanced the uptake of T 4 by cultured fibroblasts in which the LDL receptors were expressed. The T 4 binding sites on apolipoproteins B-100 and E, as well as apoA-I, have been partially characterized, and they exhibit considerable homology. A number of possible physiologic consequences of thyroid hormonelipoprotein interactions have been put forward as topics for further investigation.
TL;DR: The multihormonal control of BAT type-II 5′-deiodinase and the marked influence of T3 on UCP and BAT thermogenesis suggest that the local control of T 3 generation may be an important source of variability in the potential of mammals to maintain temperature and dissipate energy.
Abstract: Facultative (adaptive) thermogenesis is primarily controlled by the sympathetic nervous system (SNS). The participation of thyroid hormones in adaptive thermogenesis has been considered minor or, at most, permissive. The finding of type II-thyroxine (T 4 ) 5′-deiodinase in brown adipose tissue (BAT) has opened a way to uncover a more important role for thyroid hormone in adaptive thermogenesis. This enzyme is activated by the. SNS and insulin. When activated, it generates high BAT concentrations of triiodothyronine (T 3 ) from plasma T 4 . T 3 , intrinsically 10 times more active than T 4 , has been shown essential for the expression of the key protein in BAT thermogenesis, uncoupling protein (UCP). The multihormonal control of BAT type-II 5′-deiodinase and the marked influence of T 3 on UCP and BAT thermogenesis suggest that the local control of T 3 generation may be an important source of variability in the potential of mammals to maintain temperature and dissipate energy.
TL;DR: Understanding of the gonadotropic control of inhibin/activin gene expression within the various compartments of the primate ovary is enhanced before the question of whether inhibin has an endocrine function during the menstrual cycle and how cyclic reinitiation of follicular development is controlled is resolved.
Abstract: Inhibin (α-β heterodimer) has been considered to be the principal nonsteroidal ovarian regulator of pituitary FSH secretion. The β-β heterodimer, activin, produced by the ovary and other tissues, appears to act locally, with actions opposite to those of inhibin. Since immunoreactive inhibin is highest during the luteal phase of the menstrual cycle when FSH is lowest, a negative feedback role in controlling FSH release at this time has been suggested. Attempts to establish this by using immunoneutralization techniques have failed to reveal such a role. We must enhance our understanding of the gonadotropic control of inhibin/activin gene expression within the various compartments of the primate ovary, the role of their binding proteins, and the nature of the secretory products before we can resolve the question of whether inhibin has an endocrine function during the menstrual cycle and how cyclic reinitiation of follicular development is controlled.
TL;DR: All steroid receptors are phosphoproteins and several, including progesterone receptors (PRs), become hyperphosphorylated upon binding of ligand, but the functional significance of this phosphorylation cascade remains unclear.
Abstract: All steroid receptors are phosphoproteins and several, including progesterone receptors (PRs), become hyperphosphorylated upon binding of ligand. PR phosphorylation is complex, occurring in different cellular compartments and perhaps requiring multiple serine kinases. A model that is emerging proposes that PR phosphorylation is progressive, occurring in at least a three-stage cascade. However, the functional significance of this phosphorylation cascade remains unclear.
TL;DR: This review deals with the development of transgenic rodent models of the more common, classically defined human endocrine abnormalities, and the ability to introduce relatively specific and (sometimes) subtle genetic changes into rodents provides an opportunity to test hypotheses concerning primary events in human end hormones.
Abstract: Although the primary etiology of some endocrine diseases is obvious, for many of them the initiating abnormality is not known. Usually this uncertainty is due to a slow development of significant clinical symptoms, combined with the fact that an abnormality in any one endocrine gland will lead to secondary endocrine abnormalities. The ability to introduce relatively specific and (sometimes) subtle genetic changes into rodents provides an opportunity to test hypotheses concerning primary events in human endocrine disorders. This review deals with the development of transgenic rodent models of the more common, classically defined human endocrine abnormalities.